tbuckley/cabot-search huggingface dataset:
From real-world electronic health record data to real-world results using artificial intelligence
Authors: Rachel Knevel, Katherine P Liao
Journal: Annals of the Rheumatic Diseases (2022)

With the worldwide digitalisation of medical records, electronic health records (EHRs) have become an increasingly important source of real-world data (RWD). RWD can complement traditional study designs because it captures almost the complete variety of patients, leading to more generalisable results. For rheumatology, these data are particularly interesting as our diseases are uncommon and often take years to develop. In this review, we discuss the following concepts related to the use of EHR for research and considerations for translation into clinical care: EHR data contain a broad collection of healthcare data covering the multitude of real-life patients and the healthcare processes related to their care. Machine learning (ML) is a powerful method that allows us to leverage a large amount of heterogeneous clinical data for clinical algorithms, but requires extensive training, testing, and validation. Patterns discovered in EHR data using ML are applicable to real life settings, however, are also prone to capturing the local EHR structure and limiting generalisability outside the EHR(s) from which they were developed. Population studies on EHR necessitates knowledge on the factors influencing the data available in the EHR to circumvent biases, for example, access to medical care, insurance status. In summary, EHR data represent a rapidly growing and key resource for real-world studies. However, transforming RWD EHR data for research and for real-world evidence using ML requires knowledge of the EHR system and their differences from existing observational data to ensure that studies incorporate rigorous methods that acknowledge or address factors such as access to care, noise in the data, missingness and indication bias.
IOC consensus statement on recommendations and regulations for sport events in the heat
Authors: Sebastien Racinais, Yuri Hosokawa, Takao Akama, Stephane Bermon, Xavier Bigard, Douglas J Casa, Andrew Grundstein, Ollie Jay, Andrew Massey, Sergio Migliorini, Margo Mountjoy, Nebosa Nikolic, Yannis P Pitsiladis, Wolfgang Schobersberger, Juergen Michael Steinacker, Fumihiro Yamasawa, David Anthony Zideman, Lars Engebretsen, Richard Budgett
Journal: British Journal of Sports Medicine (2022)

This document presents the recommendations developed by the IOC Medical and Scientific Commission and several international federations (IF) on the protection of athletes competing in the heat. It is based on a working group, meetings, field experience and a Delphi process. The first section presents recommendations for event organisers to monitor environmental conditions before and during an event; to provide sufficient ice, shading and cooling; and to work with the IF to remove regulatory and logistical limitations. The second section summarises recommendations that are directly associated with athletes' behaviours, which include the role and methods for heat acclimation; the management of hydration; and adaptation to the warm-up and clothing. The third section explains the specific medical management of exertional heat stroke (EHS) from the field of play triage to the prehospital management in a dedicated heat deck, complementing the usual medical services. The fourth section provides an example for developing an environmental heat risk analysis for sport competitions across all IFs. In summary, while EHS is one of the leading life-threatening conditions for athletes, it is preventable and treatable with the proper risk mitigation and medical response. The protection of athletes competing in the heat involves the close cooperation of the local organising committee, the national and international federations, the athletes and their entourages and the medical team.
Strategies to prevent and manage running-related knee injuries: a systematic review of randomised controlled trials
Authors: James L N Alexander, Adam G Culvenor, Richard R T Johnston, Allison M Ezzat, Christian J Barton
Journal: British Journal of Sports Medicine (2022)

To evaluate the effectiveness of interventions to prevent and manage knee injuries in runners.Systematic review and meta-analysis.MEDLINE, EMBASE, CINAHL, Web of Science and SPORTDiscus up to May 2022.Randomised controlled trials (RCTs) with a primary aim of evaluating the effectiveness of intervention(s) to prevent or manage running-related knee injury.Thirty RCTs (18 prevention, 12 management) analysed multiple interventions in novice and recreational running populations. Low-certainty evidence (one trial, 320 participants) indicated that running technique retraining (to land softer) reduced the risk of knee injury compared with control treadmill running (risk ratio (RR) 0.32, 95% CI 0.16 to 0.63). Very low-certainty to low-certainty evidence from 17 other prevention trials (participant range: 24 -3287) indicated that various footwear options, multicomponent exercise therapy, graduated running programmes and online and in person injury prevention education programmes did not influence knee injury risk (RR range: 0.55-1.06). In runners with patellofemoral pain, very low-certainty to low-certainty evidence indicated that running technique retraining strategies, medial-wedged foot orthoses, multicomponent exercise therapy and osteopathic manipulation can reduce knee pain in the short-term (standardised mean difference range: -4.96 to -0.90).There is low-certainty evidence that running technique retraining to land softer may reduce knee injury risk by two-thirds. Very low-certainty to low-certainty evidence suggests that running-related patellofemoral pain may be effectively managed through a variety of active (eg, running technique retraining, multicomponent exercise therapy) and passive interventions (eg, foot orthoses, osteopathic manipulation).CRD42020150630.
Dysregulated stem cell niches and altered lymphocyte recirculation cause B and T cell lymphopenia in WHIM syndrome
Authors: Sandra Zehentmeier, Vivian Y. Lim, Yifan Ma, Julia Fossati, Takeshi Ito, Yawen Jiang, Alexei V. Tumanov, Ho-Joon Lee, Lukas Dillinger, Jihyun Kim, Krisztian Csomos, Jolan E. Walter, Jungmin Choi, João P. Pereira
Journal: Science Immunology (2022)

Gain-of-function (GOF) mutations in CXCR4 cause WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome, characterized by infections, leukocyte retention in bone marrow (BM), and blood leukopenias. B lymphopenia is evident at early progenitor stages, yet why do CXCR4 GOF mutations that cause B (and T) lymphopenia remain obscure? Using a CXCR4 R334X GOF mouse model of WHIM syndrome, we showed that lymphopoiesis is reduced because of a dysregulated mesenchymal stem cell (MSC) transcriptome characterized by a switch from an adipogenic to an osteolineage-prone program with limited lymphopoietic activity. We identify lymphotoxin beta receptor (LTβR) as a critical pathway promoting interleukin-7 (IL-7) down-regulation in MSCs. Blocking LTβR or CXCR4 signaling restored IL-7 production and B cell development in WHIM mice. LTβR blocking also increased production of IL-7 and B cell activating factor (BAFF) in secondary lymphoid organs (SLOs), increasing B and T cell numbers in the periphery. These studies revealed that LTβR signaling in BM MSCs and SLO stromal cells limits the lymphocyte compartment size.
A Stk4-Foxp3–NF-κB p65 transcriptional complex promotes T <sub>reg</sub> cell activation and homeostasis
Authors: Ye Cui, Mehdi Benamar, Klaus Schmitz-Abe, Varsha Poondi-Krishnan, Qian Chen, Bat-Erdene Jugder, Benoit Fatou, Jason Fong, Yuelin Zhong, Stuti Mehta, Altantsetseg Buyanbat, Beray Selver Eklioglu, Esra Karabiber, Safa Baris, Ayca Kiykim, Sevgi Keles, Emmanuel Stephen-Victor, Claudia Angelini, Louis-Marie Charbonnier, Talal A. Chatila
Journal: Science Immunology (2022)

The molecular programs involved in regulatory T (Treg) cell activation and homeostasis remain incompletely understood. Here, we show that T cell receptor (TCR) signaling in Treg cells induces the nuclear translocation of serine/threonine kinase 4 (Stk4), leading to the formation of an Stk4-NF-κB p65-Foxp3 complex that regulates Foxp3- and p65-dependent transcriptional programs. This complex was stabilized by Stk4-dependent phosphorylation of Foxp3 on serine-418. Stk4 deficiency in Treg cells, either alone or in combination with its homolog Stk3, precipitated a fatal autoimmune lymphoproliferative disease in mice characterized by decreased Treg cell p65 expression and nuclear translocation, impaired NF-κB p65-Foxp3 complex formation, and defective Treg cell activation. In an adoptive immunotherapy model, overexpression of p65 or the phosphomimetic Foxp3S418E in Stk3/4-deficient Treg cells ameliorated their immune regulatory defects. Our studies identify Stk4 as an essential TCR-responsive regulator of p65-Foxp3-dependent transcription that promotes Treg cell-mediated immune tolerance.
Wide-area transepithelial sampling with computer-assisted analysis to detect high grade dysplasia and cancer in Barrettʼs esophagus: a multicenter randomized study
Authors: Sanne N. van Munster, Philippe Leclercq, Rehan Haidry, Helmut Messmann, Andreas Probst, Krish Ragunath, Pradeep Bhandari, Alessandro Repici, Miguel Munoz-Navas, Stefan Seewald, Arnaud Lemmers, Glòria Fernández-Esparrach, Oliver Pech, Erik J. Schoon, Revital Kariv, Horst Neuhaus, Bas L. A. M. Weusten, Peter D. Siersema, Loredana Correale, Sybren L. Meijer, Gert de Hertogh, Jacques J.G.H.M. Bergman, Cesare Hassan, Raf Bisschops
Journal: Endoscopy (2022)

Background Current surveillance for Barrett’s esophagus (BE), consisting of four-quadrant random forceps biopsies (FBs), has an inherent risk of sampling error. Wide-area transepithelial sampling (WATS) may increase detection of high grade dysplasia (HGD) and esophageal adenocarcinoma (EAC). In this multicenter randomized trial, we aimed to evaluate WATS as a substitute for FB. Methods Patients with known BE and a recent history of dysplasia, without visible lesions, at 17 hospitals were randomized to receive either WATS followed by FB or vice versa. All WATS samples were examined, with computer assistance, by at least two experienced pathologists at the CDx Diagnostics laboratory. Similarly, all FBs were examined by two expert pathologists. The primary end point was concordance/discordance for detection of HGD/EAC between the two techniques. Results 172 patients were included, of whom 21 had HGD/EAC detected by both modalities, 18 had HGD/EAC detected by WATS but missed by FB, and 12 were detected by FB but missed by WATS. The detection rate of HGD/EAC did not differ between WATS and FB (P = 0.36). Using WATS as an adjunct to FB significantly increased the detection of HGD/EAC vs. FB alone (absolute increase 10 % [95 %CI 6 % to 16 %]). Mean procedural times in minutes for FB alone, WATS alone, and the combination were 6.6 (95 %CI 5.9 to 7.1), 4.9 (95 %CI 4.1 to 5.4), and 11.2 (95 %CI 10.5 to 14.0), respectively. Conclusions Although the combination of WATS and FB increases dysplasia detection in a population of BE patients enriched for dysplasia, we did not find a statistically significant difference between WATS and FB for the detection of HGD/EAC as single modality.
Integrative analysis identifies an older female-linked AML patient group with better risk in ECOG-ACRIN Cancer Research Group’s clinical trial E3999
Authors: Franck Rapaport, Kenneth Seier, Yaseswini Neelamraju, Duane Hassane, Timour Baslan, Daniel T. Gildea, Samuel Haddox, Tak Lee, H. Moses Murdock, Caroline Sheridan, Alexis Thurmond, Ling Wang, Martin Carroll, Larry D. Cripe, Hugo Fernandez, Christopher E. Mason, Elisabeth Paietta, Gail J. Roboz, Zhuoxin Sun, Martin S. Tallman, Yanming Zhang, Mithat Gönen, Ross Levine, Ari M. Melnick, Maria Kleppe, Francine E. Garrett-Bakelman
Journal: Blood Cancer Journal (2022)
Targeting STAT5 Signaling Overcomes Resistance to IDH Inhibitors in Acute Myeloid Leukemia through Suppression of Stemness
Authors: Alex C.H. Liu, Severine Cathelin, Yitong Yang, David L. Dai, Dhanoop Manikoth Ayyathan, Mohsen Hosseini, Mark D. Minden, Anne Tierens, Steven M. Chan
Journal: Cancer Research (2022)

Abstract Mutant isocitrate dehydrogenase 1 (IDH1) and IDH2 block the differentiation of acute myeloid leukemia (AML) cells through production of R-2-hydroxyglutarate (R-2-HG). IDH inhibitors can induce differentiation of AML cells by lowering R-2-HG but have limited clinical efficacy as single agents. Here, we performed a genome-wide CRISPR knockout screen in an Idh1-mutated hematopoietic progenitor cell line to identify genes that increased the differentiation response to ivosidenib, an IDH1 inhibitor. The screen identified C-type lectin member 5a (Clec5a), which encodes a spleen tyrosine kinase (SYK)-coupled surface receptor, as one of the top hits. Knockout of Clec5a and Syk rendered cells more sensitive to ivosidenib-induced differentiation through a reduction in STAT5-dependent expression of stemness-related genes, including genes in the homeobox (HOX) family. Importantly, direct inhibition of STAT5 activity was sufficient to increase the differentiation response to IDH inhibitors in primary human IDH1- and IDH2-mutated AML cells, including those harboring mutations in receptor tyrosine kinase (RTK) and MAPK genes that have been linked to drug resistance. In patient-derived xenograft models of IDH1-mutated AML, combination treatment with ivosidenib and the STAT5 inhibitor pimozide was superior to each agent alone in inducing differentiation in leukemic cells without compromising normal hematopoiesis. These findings demonstrate that STAT5 is a critical mediator of resistance to IDH inhibitors and provide the rationale for combining STAT5 and IDH inhibitors in the treatment of IDH-mutated AML. Significance: A CRISPR knockout screen identifies a mechanism of resistance to IDH inhibitors in AML involving activated STAT5 signaling, suggesting a potential strategy to improve the clinical efficacy of IDH inhibitors.
Systematic Review and Network Meta-analysis of Neurostimulation for Painful Diabetic Neuropathy
Authors: Rui V. Duarte, Sarah Nevitt, Sue Copley, Michelle Maden, Cecile C. de Vos, Rod S. Taylor, Sam Eldabe
Journal: Diabetes Care (2022)

BACKGROUND Different waveforms of spinal cord stimulation (SCS) have now been evaluated for the management of painful diabetic neuropathy (PDN). However, no direct or indirect comparison between SCS waveforms has been performed to date. PURPOSE To conduct a systematic review and network meta-analysis to evaluate the effectiveness of SCS for PDN. DATA SOURCES MEDLINE, CENTRAL, Embase, and WikiStim were searched from inception until December 2021. STUDY SELECTION Randomized controlled trials (RCTs) of SCS for PDN were included. DATA EXTRACTION Pain intensity, proportion of patients achieving at least a 50% reduction in pain intensity, and health-related quality of life (HRQoL) data were extracted. DATA SYNTHESIS Significant reductions in pain intensity were observed for low-frequency SCS (LF-SCS) (mean difference [MD] −3.13 [95% CI −4.19 to −2.08], moderate certainty) and high-frequency SCS (HF-SCS) (MD −5.20 [95% CI −5.77 to −4.63], moderate certainty) compared with conventional medical management (CMM) alone. There was a significantly greater reduction in pain intensity on HF-SCS compared with LF-SCS (MD −2.07 [95% CI −3.26 to −0.87], moderate certainty). Significant differences were observed for LF-SCS and HF-SCS compared with CMM for the outcomes proportion of patients with at least 50% pain reduction and HRQoL (very low to moderate certainty). No significant differences were observed between LF-SCS and HF-SCS (very low to moderate certainty). LIMITATIONS Limited number of RCTs and no head-to-head RCTs conducted. CONCLUSIONS Our findings confirm the pain relief and HRQoL benefits of the addition of SCS to CMM for patients with PDN. However, in the absence of head-to-head RCT evidence, the relative benefits of HF-SCS compared with LF-SCS for patients with PDN remain uncertain.
Innovative Designs and Logistical Considerations for Expedited Clinical Development of Combination Disease-Modifying Treatments for Type 1 Diabetes
Authors: Randy L. Anderson, Linda A. DiMeglio, Adrian P. Mander, Colin M. Dayan, Peter S. Linsley, Kevan C. Herold, Marjana Marinac, Simi T. Ahmed
Journal: Diabetes Care (2022)

It has been 100 years since the life-saving discovery of insulin, yet daily management of type 1 diabetes (T1D) remains challenging. Even with closed-loop systems, the prevailing need for persons with T1D to attempt to match the kinetics of insulin activity with the kinetics of carbohydrate metabolism, alongside dynamic life factors affecting insulin requirements, results in the need for frequent interventions to adjust insulin dosages or consume carbohydrates to correct mismatches. Moreover, peripheral insulin dosing leaves the liver underinsulinized and hyperglucagonemic and peripheral tissues overinsulinized relative to their normal physiologic roles in glucose homeostasis. Disease-modifying therapies (DMT) to preserve and/or restore functional β-cell mass with controlled or corrected autoimmunity would simplify exogenous insulin need, thereby reducing disease mortality, morbidity, and management burdens. However, identifying effective DMTs for T1D has proven complex. There is some consensus that combination DMTs are needed for more meaningful clinical benefit. Other complexities are addressable with more innovative trial designs and logistics. While no DMT has yet been approved for marketing, existing regulatory guidance provides opportunities to further "de-risk" development. The T1D development ecosystem can accelerate progress by using more innovative ways for testing DMTs for T1D. This perspective outlines suggestions for accelerating evaluation of candidate T1D DMTs, including combination therapies, by use of innovative trial designs, enhanced logistical coordination of efforts, and regulatory guidance for expedited development, combination therapies, and adaptive designs.
Reply to D.J. Benedetti et al
Authors: Steven G. DuBois, Abha A. Gupta, Emanuela Palmerini
Journal: Journal of Clinical Oncology (2022)

are correct that we should have stated in our editorial 2 that the standard of care for this high-risk population with widely metastatic Ewing sarcoma should be to offer participation in clinical trials when available.We will take this opportunity to point out that the regimens used in patients with advanced disease are often extrapolated from those demonstrating benefit in patients with localized disease. 2 Unfortunately, these regimens yield unsatisfactory outcomes in approximately four of five patients, and these outcomes have not improved in decades.
Poly(ADP-Ribose) Polymerase Inhibitors in the Management of Ovarian Cancer: ASCO Guideline Rapid Recommendation Update
Authors: William P. Tew, Christina Lacchetti, Elise C. Kohn
Journal: Journal of Clinical Oncology (2022)

ASCO Rapid Recommendations Updates highlight revisions to select ASCO guideline recommendations as a response to the emergence of new and practice-changing data. The rapid updates are supported by an evidence review and follow the guideline development processes outlined in the ASCO Guideline Methodology Manual. The goal of these articles is to disseminate updated recommendations, in a timely manner, to better inform health practitioners and the public on the best available cancer care options.
Response to Comment on Mone et al. Empagliflozin Improves Cognitive Impairment in Frail Older Adults With Type 2 Diabetes and Heart Failure With Preserved Ejection Fraction. Diabetes Care 2022;45:1247–1251
Authors: Gaetano Santulli, Salvatore Frullone, Maria Morgante, Gaetano Macina, Antonella Pansini, Jessica Gambardella, Angela Lombardi, Pasquale Mone
Journal: Diabetes Care (2022)
When I use a word . . . . Too much healthcare—uncertainty, underconfidence, and masterly inactivity
Authors: Jeffrey K Aronson
Journal: BMJ (2022)

Underconfidence is as important to too much healthcare as its counterpart, overconfidence, and both are linked to uncertainty. Uncertainty in clinical medicine can be alleviated to some extent by gathering evidence, from the history, examination, and investigations. However, when further investigations become unlikely to yield more certainty, the less confident an individual is about interpreting the available information in order to reach a decision, the more likely they will be to pursue unnecessary, and potentially harmful, investigations. The problem is exacerbated by the fact that most people are unable to assess their own degree of confidence and therefore the extent of their own uncertainty and how much more evidence they would need to make them sufficiently certain to proceed. As the Fat Man argues in Samuel Shem’s satirical novel <i>The House of God</i> (1978), the best medicine is to do as much nothing as possible—masterly inactivity, akin to primum est ut non nocere. Clinical medicine is riddled with uncertainty, and many have difficulty in coping with it. The overconfident arrogantly brush it aside. The underconfident may be paralysed by it, unable to decide what’s best.
A multidisciplinary approach to the diagnosis and management of Wilson disease: 2022 Practice Guidance on Wilson disease from the American Association for the Study of Liver Diseases
Authors: Michael L. Schilsky, Eve A. Roberts, Jeff M. Bronstein, Anil Dhawan, James P. Hamilton, Anne Marie Rivard, Mary Kay Washington, Karl Heinz Weiss, Paula C. Zimbrean
Journal: Hepatology (2022)

Schilsky, Michael L.; Roberts, Eve A.; Bronstein, Jeff M.; Dhawan, Anil; Hamilton, James P.; Rivard, Anne Marie; Washington, Mary Kay; Weiss, Karl Heinz; Zimbrean, Paula C. Author Information
Pharmacological Interventions in Labor and Delivery
Authors: Susan Wray, Sarah Arrowsmith, Andrew Sharp
Journal: The Annual Review of Pharmacology and Toxicology (2022)

While there is not a wide range of pregnancy-specific drugs, there are some very specific high-risk areas of obstetric care for which unique pharmacological approaches have been established. In preterm birth, labor induction and augmentation, and the management of postpartum hemorrhage, these pharmacological approaches have become the bedrock in managing some of the most common and problematic areas of antenatal and intrapartum care. In this review, we summarize the existing established and emerging evidence that supports and broadens these pharmacological approaches to obstetric management and its impact on clinical practice. It is clear that existing therapeutics are limited. They have largely been developed from our knowledge of the physiology of the myometrium and act on hormonal receptors and their signaling pathways or on ion channels influencing excitability. Newer drugs in development are mostly refinements of these two approaches, but novel agents from plants and improved formulations are also discussed.